Manning, Sawyer and coworkers have published a series of publications describing various vasopressin structures having a Pmp unit at position 1. Representative of these are U.S. Pat. Nos. 4,367,225 or 4,399,125 as well as Nature, 308 652 (1984).
Tryptophan is, of course, known to be a unit in other peptides such as the somatostatins (U.S. Pat. No. 4,320,214). It was also inserted at position 2 of oxytocin to give a compound with reduced oxytocic effect, M. Lebl et al., Proceedings of the 7th European Peptide Symposium, 1982.
The VSP antagonist compounds of the present invention have, at either the 2 or 3 position of their structures, a .beta.-indolylalanyl or a .beta.-indolylglycine. No VSP peptides to the best of my knowledge have been reported previously which have structures having a unit derived from an aromatic, bicyclic heterocyclic containing amino acid.
Certain of the peptide art designations used in the specification and claims are the following: Cap, .beta.-mercapto-.beta.,.beta.-cycloalkylenepropionic acid; Pmp, .beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid; Chg, cyclohexylglycine; Abu, .alpha.-amino-n-butyric acid; Cha, cyclohexylalanine; Tyr, tyrosine; Tyr(Alk), O-alkyltyrosine; Phe, phenylalanine; Phe(4'-Alk), lower alkylphenylalanine; Val, valine; Nva, norvaline; Ile, isoluecine; Nle, norleucine; Leu, leucine; Ala, alanine; Lys, lysine; Arg, arginine; Harg, homoarginine; Asn, asparagine; Tos, tosylate; HF, hydrogen fluoride; BHA, benzhydrylamine; DIEA, diisopropylethylamine; 4-MeBzl, 4-methylbenzyl; TFA, trifluoroacetic acid; DCC, dicyclohexylcarbodiimide; HBT, 1-hydroxybenzotriazole; ADH, antidiuretic hormone; ACM, acetamidomethyl; DMAP, dimethylaminopyridine.
When the terms "vasopressin" or "VSP" are used, in the specification only, they mean L-arginine vasopressin (AVP) unless otherwise modified. The AVP derivatives of this invention are preferred. "Alk" represents a lower alkyl of 1-4 carbons which is optionally attached to the amide nitrogen at Y, to the oxygen substituent of the tyrosine unit when such is present at position 2 or to the phenyl ring of a phenylalanine unit such as at ring positions 2 or 3. Such alkyl substituents include methyl, ethyl, n-propyl, isopropyl or butyl.
Therefore, in the description herein and in the claims, the nomenclature common in the art of peptide and vasopressin chemistry is used. In certain designations such as the sulfur ring members, the key structural feature may be added for clarity. When no configuration is noted, the amino acid unit is in the L, or naturally occurring, form.